Pharmacokinetics of Dolutegravir in Children With HIV With and Without Tuberculosis Coinfection Treated According to World Health Organization Dosing Guidelines.

BACKGROUND

The pharmacokinetics (PK) and safety of dolutegravir (DTG) in children with HIV (CWH) weighing at least 20 kg with and without tuberculosis (TB) treated according to World Health Organization dosing guidelines was examined.

METHODS

CWH on DTG 50 mg once-daily and those with HIV/TB on 50 mg twice-daily with rifampin-based therapy were enrolled. Five to 6 blood samples were collected within the dosing interval after 4 weeks (period-1) and 7-8 months (period-2) of DTG-based therapy. Dolutegravir concentrations were measured using liquid chromatography tandem with mass spectrometry (LC/MS/MS) and PK parameters calculated by noncompartmental analysis. Geometric mean ratio (GMR) with 95% confidence interval was used to compare PK parameters on and off TB treatment and between the 2 groups.

RESULTS

Of 25 participants, 52% had TB coinfection. Rifampin coadministration increased DTG clearance by 86%. GMRs (95% confidence interval) of area under the concentration-time curve (AUC 0-24h ) and trough concentration (C trough ) of DTG twice-daily with rifampin versus once-daily alone were 1.07 (0.79-1.44) and 1.45 (0.89-2.35), respectively. Comparing HIV/TB versus HIV, DTG AUC 0-24h and C trough GMRs (respectively) were 1.69 (0.99-2.90) and 2.50 (1.19-5.26) in period-1 and 1.26 (0.85-1.85) and 1.57 (0.53-4.68) in period-2. Two participants with HIV and none with HIV/TB had C trough <0.32 mg/L. Overall, 92% of participants with HIV/TB and 82% with HIV achieved viral load <400 copies/mL at 6 months of DTG-based therapy, with no DTG discontinuations.

CONCLUSIONS

Twice-daily DTG with rifampin was associated with higher trough concentrations in CWH/TB than in controls. Standard dose of DTG with rifampin needs to be investigated.